The present invention relates to an inclusion complex formed between cyclodextrin and drospirenone, to methods of providing such an inclusion complex, and to a method of increasing the water solubility of drospirenone by providing such an inclusion complex. Moreover, the present invention relates to the use of said inclusion complex in pharmaceutical compositions for use as a medicament in the treatment of symptoms associated with menopause and in female contraception.
Drospirenone (6xcex2,7xcex2;15xcex2,16xcex2-dimethylene-3-oxo-17xcex1-pregn-4-ene-21,17-carbolactone), which may be prepared substantially as described in e.g. U.S. Pat. No. 4,129,564 or WO 98/06738, is only sparingly soluble in aqueous media at various pH values.
The water solubility of a compound is extremely pertinent with regards to its utility in industry, particularly in the pharmaceutical industry where there is a strong link between water solubility and bioavailability. The therapeutic efficiency of drospirenone may be improved by increasing its overall water solubility, thus providing for routes of administration alternative to those proceeding via the gastrointestinal tract, where absorption is slow and then rapidly cleared from circulating blood by the liver.
Cyclodextrins are known to solubilize nonpolar compounds and improve the absorption of certain compounds by forming complexes with said compounds. The cyclodextrins are frequently derivatized in order to improve the solubility or to accommodate appropriately the compound of interest. However, certain compounds are not well accommodated by the cavity of the some of the cyclodextrin molecules.
Drospirenone, in its uncomplexed form, is known from DE 26 52 761 in which its use as a diuretic compound is disclosed.
U.S. Pat. No. 4,596,795 discloses a complex between xcex1-, xcex2- and xcex3-cyclodextrins and derivatives thereof with testosterone, progesterone, and estradiol and the solubility of said complexes.
U.S. Pat. No. 5,885,978 relates to a composition comprising an adrenal cortical steroid and cyclodextrin prepared by clathrating the adrenal cortical steroid in the cyclodextrin using a homomixer.
U.S. Pat. No. 5,376,641 discloses a method of making a steroid water soluble by mixing a steroid and a branched beta cyclodextrin together in water for a period of 4 to 24 hours under ambient conditions.
U.S. Pat. No. 5,376,641 discloses a method for making a steroid water soluble by complexing the steroid with branched xcex2-cyclodextrin.
U.S. Pat. No. 4,727,064 discloses a method of improving the dissolution properties of a steroid by forming a solid comprising at least one of testosterone, progesterone and estradiol as an inclusion complex with a poly-xcex2-cyclodextrin and /or hydroxypropyl-xcex2-cyclodextrin adapted for administration by buccal route.
FR 2 515 187 discloses inclusion complexes between xcex3-cyclodextrines and various steroids, such as a spironolactone steroid.
WO 96/02277 discloses pharmaceutical compositions containing cyclodextrin-clathrate complexes of steroid sexual hormones for protection against oxidative degradation of steroids.
The invention relates to an inclusion complex between cyclodextrin and 6xcex2,7xcex2;15xcex2,16xcex2-dimethylene-3-oxo-17xcex1-pregn-4-ene-21,17-carbolactone (drospirenone).
The invention also relates to methods for producing an inclusion complex between cyclodextrin and drospirenone comprising combining drospirenone and cyclodextrin at a molar ratio of from 0.3:1 to 20:1, preferably 1:1, 2:1, 3:1, 4:1 or 5:1, most preferably 2:1 or 3:1, particularly 3:1.
One object of the present invention is to increase the water-solubility of drospirenone. The present invention thus further relates to methods for improving the solubility of drospirenone, said method comprising forming an inclusion complex between drospirenone and cyclodextrin.
In a further aspect of the invention, pharmaceutical compositions comprising an inclusion complex of drospirenone and cyclodextrin are anticipated. Consequently, the use of the inclusion complex between drospirenone and cyclodextrin as a medicament and for the preparation of a composition for female contraception or for the treatment of menopausal symptoms are defined herein. Upon further study of the specification and appended claims, further objects and advantages of this invention will become apparent to those skilled in the art.
The term xe2x80x9cinclusion complexxe2x80x9d is intended to mean a complex wherein at least a moiety of drospirenone has inserted itself, at least partially, into the cavity of cyclodextrin.
In efforts to improve the functional utility of drospirenone, research has led to a new chemical entity, an inclusion complex between cyclodextrin and drospirenone. The cyclodextrin, may be selected from xcex1-cyclodextrin, xcex2-cyclodextrin, xcex3-cyclodextrin or derivatives thereof. Preferred embodiments of the present invention are that of a complex between drospirenone and xcex2-cyclodextrin or derivatives thereof or a complex between drospirenone and xcex3-cyclodextrin or derivatives thereof, most preferably a complex between drospirenone and xcex2-cyclodextrin or xcex3-cyclodextrin, particularly xcex2-cyclodextrin.
The cyclodextrin, as stated, may be selected from the group comprised of xcex1-cyclodextrin, xcex2-cyclodextrin or xcex3-cyclodextrin, i.e. the 6-, 7-, or 8-sugar unit macrocycle, respectively. The cyclodextrin may be modified such that some or all of the primary or secondary hydroxyls of the macrocyle, or both, may be alkylated or acylated. Methods of modifying these alcohols are well known to the person skilled in the art and many derivatives are commercially available. The cyclodextrin may be modified such that one or more of the primary or secondary hydroxyls of the macrocyle, or both, may be alkylated or acylated. Methods of modifying these alcohols are well known to the person skilled in the art and many are commercially available. Thus, some or all of the hydroxyls of cyclodextrin may be substituted with an Oxe2x80x94R group or an Oxe2x80x94C(O)xe2x80x94R, wherein R is an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C2-6 alkynyl, an optionally substituted aryl or heteroaryl group. R may be methyl, ethyl, propyl, butyl, pentyl, or hexyl group. Consequently, Oxe2x80x94C(O)xe2x80x94R may be an acetate. Furthermore, R may be such as to derivatize cyclodextrin with the commonly employed 2-hydroxyethyl group, or 2-hydroxypropyl group. Moreover, the cyclodextrin alcohols may be per-benzylated, per-benzoylated, or benzylated or benzoylated on just one face of the macrocycle, or wherein only 1, 2, 3, 4, 5, or 6 hydroxyls are benzylated or benzoylated. The hydroxyl groups of cyclodextrin may be per-alkylated or per-acylated such as per-methylated or per-acetylated, or alkylated or acylated, such as methylated or acetylated, on just one face of the macrocycle, or wherein only 1, 2, 3, 4, 5, or 6 hydroxyls are alkylated or acylated, such as methylated or acetylated.
In a preferred embodiment of the invention, the inclusion complex is between xcex2-cyclodextrin or xcex3-cyclodextrin and drospirenone. Most preferably, the inclusion complex is between xcex2-cyclodextrin and drospirenone and in a further interesting embodiment thereof, the xcex2-cyclodextrin is unmodified.
One or more drospirenone molecules may be included into the cavity of the cyclodextrin molecule. Conversely, one molecule of drospirenone may be included into the cavity of one or more cyclodextrin molecules. The inclusion complex may exist in a variety of molar ratios. The molar ratio between drospirenone and the cyclodextrin is dependent on a variety of physical factors during the formation of the inclusion complex. Furthermore, the molar ratio of the inclusion complex may be transitional and vary during its preparation. Given the inclusion of drospirenone can result from a variety of interactions with any number of functional groups or moieties of drospirenone, the depth at which drospirenone is included within the cavity of a cyclodextrin may vary. Furthermore, the size of the cavity, which depends on the selection of cyclodextrin (xcex1-cyclodextrin, xcex2-cyclodextrin or xcex3-cyclodextrin) and on whether the numerous free hydroxyl groups present on the periphery of the cavity of a cyclodextrin molecule are partially or fully derivatized, will influence the ability for drospirenone to include itself into the cavity. These factors, amongst others, influence the molar ratio of the inclusion complex.
Without being limited to a particular manner in which the inclusion complex is formed, it is presumed that the inclusion complex is an inclusion complex wherein hydrophobic interactions favour the inclusion of hydrophobic moieties from drospirenone into the cavity of a cyclodextrin molecule, given the relative hydrophobicity of the numerous alkyl groups in the cavity of the cyclodextrin.
Given the above-stated factors, and that the moiety of the drospirenone molecule which may include itself into the cyclodextrin molecule may vary, the molar ratio between drospirenone and the cyclodextrin, respectively, may be 1:1, 2:1, 3:1, 3:2, 1:2, 2:2, 2:3 or 1:3. Preferably a 1:1 or 1:2 molar ratio exists between drospirenone and cyclodextrin; namely, one molecule of drospirenone, or a moiety thereof, is at least partially inserted into the cavity of one cyclodextrin molecule or one molecule of drospirenone, or moieties thereof, is at least partially inserted into the cavity of two molecules of cyclodextrin. Alternatively, a 2:1 molar ratio may exist between drospirenone and cyclodextrin; namely, two molecules of drospirenone, or moieties thereof, are at least partially inserted into the cavity of one cyclodextrin molecule.
The term xe2x80x9csolubilityxe2x80x9d in connection with drospirenone is intended to mean the solubility of the inclusion complex between drospirenone and cyclodextrin in water. The term xe2x80x9ctotal solubilityxe2x80x9d relates to the drospirenone concentration in a phase solubility isotherm, namely to the solubility of uncomplexed and complexed drospirenone. The xe2x80x9ctotal solubilityxe2x80x9d is a function of the cyclodextrin concentration.
Given one of the objects of the present invention is to increase the solubility and total solubility of drospirenone, it is preferred that the inclusion complex is such that the total water solubility of drospirenone at 20xc2x0 C. is increased by a factor of at least 2, such as at least 2.5, at least 3, at least 3.5, or at least 4 compared to drospirenone in an uncomplexed form.
Correspondingly, it is preferred that the total solubility of drospirenone in water at 20xc2x0 C. is increased to at least 9xc3x9710xe2x88x925 mol/L, such as at least 1xc3x9710xe2x88x924 mol/L, 2xc3x9710xe2x88x924 mol/L, 3xc3x9710xe2x88x924 mol/L or 3.5xc3x9710xe2x88x924 mol/L.
The inclusion complex may exist in the form of a hydrate containing varying amounts of water, such as between about 1% and 25% water. The degree of hydration may vary according to, amongst other reasons, the degree of substitution of the hydroxyls, the method of preparation and the molar ratio of the inclusion complex. The water content of the inclusion complex may depend on the manner in which the inclusion complex is stored, the temperature, pressure and relative humidity. Thus, any discussion on the solid state form of the drospirenone-cyclodextrin inclusion complex comprises the range of hydrates. The hydrate water is part of the crystal lattice and thus modifying the water content may change the crystal lattice and possibly some of the physical properties of the inclusion complex.
As is known to the person skilled in the art, cyclodextrin itself forms an inclusion complex with water. Thus, the cyclodextrin used in the preparation of the drospirenone-cyclodextrin inclusion complex may be in a hydrated form or in an anhydrous form.
A further object of the invention is to provide a method for producing an inclusion complex comprising the step of combining cyclodextrin and drospirenone at a molar ratio of from 0.3:1 to 20:1, preferably 1:1, 2:1, 3:1, 4:1 or 5:1, most preferably 2:1 or 3:1, particularly 3:1.
The term xe2x80x9csolutionxe2x80x9d in connection with cyclodextrin or drospirenone and in connection with the preparation of an inclusion complex is intended to comprise embodiments wherein the solute, namely cyclodextrin or drospirenone, is fully or partially dissolved in the solvent so as to form a homogenous solution, a saturated solution, a super-saturated solution, a slurry or a suspension.
In the preparation of the inclusion complex according to the present invention, the combining of the components may be done using a solution of cyclodextrin, comprising organic solvent or an aqueous solution such as water. In some embodiments of the invention, the solvent comprises a mixture of water and an organic solvent. The organic solvent may be selected from any of those commonly used in organic synthesis such as, but not limited to, THF, methylene chloride, diethyl ether, petroleum ether, ethyl acetate, dioxane, DMF, DMSO, acetone, acetonitrile, ethanol, methanol, pyridine, or combinations thereof. Preferably, the organic solvent is miscible with water. Polar solvents are preferred such as water, methanol, ethanol, DMSO, DMF, and pyridine, most preferably water or ethanol, particularly water.
A solution of cyclodextrin, as described supra, in any concentration or degree of homogeneity, may be combined with solid drospirenone. Alternatively, the cyclodextrin solution may be combined with a solution of drospirenone. In the embodiment where a solution of cyclodextrin is combined with solid drospirenone, drospirenone may be in its micronized form.
In the embodiment where a solution of cyclodextrin is combined with a solution of drospirenone, drospirenone may be fully or partly dissolved in an organic solvent or water. Organic solvents may be selected from any of those known to the person skilled in the art such as, but not limited to, THF; methylene chloride, diethyl ether, petroleum ether, ethyl acetate, dioxane, DMF, DMSO, acetone, acetonitrile, ethanol, methanol, pyridine, or combinations thereof.
It follows that a solution of drospirenone, as described supra, in any degree of homogeneity and in any concentration may be combined with solid cyclodextrin in the preparation of an inclusion complex between cyclodextrin and drospirenone.
Alternatively, solid drospirenone and solid cyclodextrin may be combined in their solid forms and then combined with water or an organic solvent.
In a preferred embodiment of the invention, a method of producing an inclusion complex comprises the steps of dissolving cyclodextrin in water, optionally with the aid of heating, to form a cyclodextrin solution; dissolving drospirenone in a solvent selected from the group comprising of water and ethanol or mixtures thereof, optionally with the aid of heating, to form a drospirenone solution; combining the cyclodextrin solution and the drospirenone solution to form a combined solution; stirring the combined solution, preferably while keeping the solution at or below 25xc2x0 C.; filtering the resultant precipitate; washing the precipitate with a solvent selected from the group consisting of water, ethanol, ether and acetone, preferably wherein the solvent is cooled to below 25xc2x0 C.; optionally suspending the resultant solid in a solvent, preferably acetone, and washing the suspended material with a solvent selected from the group consisting of water, ethanol, ether and acetone, preferably wherein the solvent is cooled to below 25xc2x0 C.; removing substantially all of the solvent from the solid material. Preferably, the solvent is removed by spray drying or alternatively by lyophilization.
The method of preparation may further comprise mechanical mixing, agitation or shaking, or heating of the solutions or combined components.
In embodiments of the invention wherein an organic solvent is used in the combination of drospirenone or cyclodextrin, the inclusion complex formed may contain one or more molecules of said solvents, depending on the method of drying, precipitation or crystallisation. The complex may alternatively exist in the form of a hydrate containing varying amounts of water.
A typical preparation of the drospirenone-cyclodextrin inclusion complex may be as follows: Drospirenone is dissolved in a solvent such as acetone or ethanol. The cyclodextrin is dissolved in water between 20 and 100xc2x0 C., such as between 30 and 90xc2x0 C., such as between 40 and 80xc2x0 C., preferably between 40 and 60xc2x0 C., such as at or near 40xc2x0 C., 45xc2x0 C., 50xc2x0 C., 55xc2x0 C. or 60xc2x0 C. The drospirenone solution is added to the cyclodextrin solution and the obtained suspension is stirred at 20-30xc2x0 C. for some hours, such as about 0.5 to 48 hours, then stirred at 2xc2x0 C. for some hours. The crystallised product is isolated and dried. In an alternative process, the drospirenone solution is added to the cyclodextrin solution and the obtained suspension is stirred at temperatures below 25xc2x0 C.
The inclusion complex may be prepared by methods described in or similar to those described in Examples 2, 3, 4, and 5.
The crystallised product may be washed with water, acetone and/or any other solvent in order to wash off non-complexed material. The solvent used to wash the crystallised product may be pre-cooled to below 25xc2x0 C. This crystallised product may be dried over a drying agent such as P2O5 or any other known to the person skilled in the art in a vacuum dessicator or cabinet for several hours or days. It may also be cooled in the dessicator during drying, or undergo spray drying or lyophillization.
A further objective of the invention is to provide a pharmaceutical composition comprising an inclusion complex of drospirenone and cyclodextrin as described supra together with one or more pharmaceutically acceptable carriers or excipients. The pharmaceutical composition may be adapted to be administered by oral, parental, mucosal, or topical, vaginal, subcutaneous or nasal administration. The composition may comprise from 0.1 mg to 10 mg of drospirenone, depending on its therapeutic application.
The drospirenone cyclodextrin inclusion complex may be used as a medicament. The drospirenone cyclodextrin inclusion complex may be used for the preparation of a pharmaceutical composition for female contraception or for the treatment of menopausal symptoms.
In suitable embodiments of the present invention, a pharmaceutical composition may comprise an inclusion complex between drospirenone and cyclodextrin and further comprise one or more therapeutically active substances. The therapeutically active substance is preferable a steroid. The therapeutically active substance may be complexed with cyclodextrin. Moreover, it may form part of an inclusion complex further comprising drospirenone. For instance, in the embodiment wherein drospirenone and cyclodextrin form an inclusion complex with a 1:2 or 1:3 molar ratio, respectively, said inclusion complex may further comprise a therapeutically active substance to form an inclusion complex with a 1:2: 1 or 1:3:1. Alternatively, said therapeutically active substance may be provide not as part of an inclusion complex. The pharmaceutical composition may comprise a drospirenone cyclodextrin inclusion complex, a therapeutically active substance such as estrogen or progestogen or a gestagen together with one or more pharmaceutically acceptable carriers or excipients.
Thus, one embodiment of the present invention is a three-component inclusion complex comprising drospirenone, one or more therapeutically active substances and cyclodextrin. The three-component complex may, for example, comprise drospirenone, cyclodextrin and a therapeutically active substance in molar ratio of 1:1:1, 1:2:1, 1:3:1, 2:2:1, 2:3:1, 2:3:2, 1:3:2. The molar ratio is limited in part by the size cavity of the cyclodextrin, by the nature of the active substance and by the size of moieties included into the cavity.
Three component complexes may be prepared by combining the therapeutically active substance in solid or solution form with either a solid or solution form of drospirenone, a solid or solution form of cyclodextrin, a solid mixture of cyclodextrin and drospirenone, or with a solution of cyclodextrin and drospirenone, namely the combined solution.
The entire disclosures of all applications, patents and publications, cited herein, and of U.S. Provisional Application Serial No. 60/256,483, filed Dec. 20, 2000, and of EP Application No. 00610134.9, filed Dec. 20, 2000, are hereby incorporated by reference.
Example 1 compares the solubility of drospirenone in water with the solubility of a sample of an inclusion complex substantially consisting of a 1:1 molar ratio between xcex2-cyclodextrin and drospirenone and to a sample consisting substantially of a 2:1 molar ratio between xcex2-cyclodextrin and drospirenone. The example illustrates the increase in solubility of drospirenone by complexation with xcex2-cyclodextrin. The example further discloses the stability of the 1:1 complex.
Examples 2 and 5 disclose two alternative methods for the preparation of a complex between drospirenone and xcex3-CD.
Examples 3 and 4 disclose two alternative methods for the preparation of a complex between drospirenone and xcex2-CD.